A convenient route to synthesize N2-(isobutyryl)-9-(carboxymethyl)guanine for aeg-PNA backbone

Article abstract of DOI:10.1080/15257770.2019.1666139

Synthesis of exclusive N²-(isobutyryl)-9-(carboxymethyl)guanine, an important moiety for peptide nucleic acid synthesis has been reported through a high-yielding reaction scheme starting from 6-chloro-2-amino purine. Crystal structures of two intermediates confirmed the formation of N9-regioisomer. This new synthetic route can potentially replace the conventional tedious method with moderate overall yield.

Full text of DOI:10.1080/15257770.2019.1666139

Nucleosides, Nucleotides and Nucleic Acids
ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: https://www.tandfonline.com/loi/lncn20
2
A convenient route to synthesize N -(isobutyryl)-9-
(carboxymethyl)guanine for aeg-PNA backbone
Dhrubajyoti Datta
2
To cite this article: Dhrubajyoti Datta (2019): A convenient route to synthesize N -(isobutyryl)-9-
carboxymethyl)guanine for aeg-PNA backbone, Nucleosides, Nucleotides and Nucleic Acids, DOI:
0.1080/15257770.2019.1666139
(
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NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
https://doi.org/10.1080/15257770.2019.1666139
2
A convenient route to synthesize N -(isobutyryl)-9-
carboxymethyl)guanine for aeg-PNA backbone
(
Dhrubajyoti Datta
Department of Chemistry, Chemical Biology Unit, Indian Institute of Science Education and
Research, Pune, India
ABSTRACT
ARTICLE HISTORY
Received 22 November 2018
Accepted 6 September 2019
2
Synthesis of exclusive N -(isobutyryl)-9-(carboxymethyl)gua-
nine, an important moiety for peptide nucleic acid synthesis
has been reported through a high-yielding reaction scheme
starting from 6-chloro-2-amino purine. Crystal structures of
two intermediates confirmed the formation of N9-regioisomer.
This new synthetic route can potentially replace the conven-
tional tedious method with moderate overall yield.
KEYWORDS
Peptide nucleic acid;
guanine; N9-regioisomer;
crystal structure
GRAPHICAL ABSTRACT
1
. Introduction
Organic biopolymer like nucleic acid is well recognized for chemical/
molecular evolution of life. Self-recognition and self-assembly of nucleic
acids are mainly driven by complementary (adenine:thymine; A:T and gua-
þ
nine:cytosine; G:C) and homo base pairings (C:C and G:G). DNA and
RNA are well known for self-assembly in nanometric dimension and have
unfurled one of the most rapidly expanding areas of research, with a wide
[
1]
range of applications from therapeutics to drug delivery and sensors.
Peptide nucleic acid (PNA) is a DNA mimic in which the sugar–phosphate
backbone is replaced by aminoethyl–glycyl (aeg) backbone to which the
CONTACT Dhrubajyoti Datta
dhrubajyoti@iiserpune.ac.in
Department of Chemistry, Chemical Biology
Unit, Indian Institute of Science Education and Research, Pune, 411008 India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lncn.
Supplementary material for this article can be accessed at https://doi.org/10.1080/15257770.2019.1666139.
ß 2019 Taylor & Francis Group, LLC

2
D. DATTA
nucleobases A/G/C/T are connected by acetyl spacer through a tertiary
[
2]
amide linkage. PNA binds to complementary DNA/RNA (cDNA/cRNA)
better than the corresponding DNA with its cDNA/cRNA and with high
[
3]
sequence specificity. Simultaneously, interesting structural motifs derive
from homomeric combinatorial G-duplex, tetraplexes (G-tetrad/G-quadru-
þ
[4]
plex) and i-motifs (C:C ) owing to various non-canonical structures.
The marked effect regioisomer on PNA backbone was demonstrated by
[
5]
D’Costa et al. when N7-G was incorporated as a protonated cytosine
mimic. Hence, unlike cytosine or pseudo-isocytosine, N7-guanine cannot
interact through Watson–Crick (W–C) hydrogen bonding. Later, duplex/
triplex formation through a (S,S)-trans-cyclopentane (tcyp) modified
PNA backbone was investigated by Englund et. al. using both N7 and
N9-guanine isomers. For aeg–G–PNA synthesis, the preparation of the
monomers requires a suitably protected aeg, and the guanine acetic acid
derivatives. Among all the nucleobase acetic acids, preparation of the guan-
[
6]
[
7]
ine acetic acid derivatives pose the greatest synthetic challenge. So far,
the only route which yielded exclusive N9-regioisomer of G-acetic acid was
[
8]
reported by Uhlmann et al.
Unfortunately, it requires N2-acetyl-O4-
[
9]
dipheylcaxbamoylguanine, a derivative of guanine which is difficult to
scale up quickly. Nevertheless, the regiomeric purity of G-PNA cannot be
compromised as N9-regioisomer is faceted to accommodate complementary
nucleobase C through either W–C or Hoogsteen site. It was reported
2
that synthesis of N -(isobutyryl)-9-(carboxymethyl)guanine 1 from guanine
is difficult due to ‘time-consuming separation process’ of N9- and N7-
[
10]
regioisomers.
However, lowering the temperature favored the formation
[
8,11]
of the desired N9-regioisomer.
The separation of N9/N7 regioisomers
through chromatographic technique is extremely laborious due to small Rf
difference between the regioisomers. To overcome these drawbacks, the
author has proposed a modified route which starts from a relatively expen-
sive purine nucleobase 6-chloro-2-aminopurine which in turn can diminish
[
7]
the selectivity problem in alkylation reactions. Earlier, N9 regioisomer of
[
12]
guanine derivatives were successfully synthesized by Harnden et al.
employing 6-chloro analogues which prompted us to revisit and attend
this problem.
2
. Results and discussion
Initially, 1 was synthesized following the literature procedure
to afford a moderate overall yield of 54% with respect to guanine 2.
[
6,10,13]
2
[14]
N -Isobutyrylguanine 3
was synthesized first from 2 which was
alkylated using NaH/tert-butylbromoacetate at low temperature to afford
[
11]
N9-alkylated derivative 4A with N7 regioisomer 4B
(Scheme 1). Desired

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
3
2
Scheme 1. Conventional synthesis of N -(isobutyryl)-9-(carboxymethyl)guanine 1.
Scheme 2. Modified synthetic route of 1 and its consequent attachment on aeg–PNA backbone.
isomer 4A was obtained after a flash column chromatography followed by
recrystallization of crude regiomeric mixture. Accumulation of two crops of
white crystals from ethyl acetate (EtOAc) within 3 days afforded 60% pure
4A. Removal of the tert-butyl ester group of 4A using trifluoroacetic acid
(
TFA) in presence of triethylsilane (TES) produced the N9-guanine acetic
acid 1 in quantitative yield.
In modified route, alkylation of 6-chloro-2-aminopurine 5 by tert-butyl-
[
15]
bromoacetate under mild basic conditions afforded N9 isomer 6
as
exclusive product with high yield at room temperature. None of the previ-
[
15]
ous literatures
did report the N9 isomer of 6 through single crystal
structure. However, structure of tert-butyl[2-(((benzyloxy)carbonyl)
[
16]
(tert-butoxycarbonyl)amino)-6-(2-nitrophenoxy)-9H-purin-9-yl]acetate,
a
derivative of 6, was reported. The author proceeded further to protect the
2
-amino group of 6 with isobutyryl chloride to afford 7 in good yield.
[
17]
2
Treatment of 7 with 50% aqueous TFA
yielded desired N -(isobutyryl)-
9-(carboxymethyl)guanine 1 with 76% overall yield with respect to 5
(Scheme 2). Guanine acetic acid thus obtained was coupled with aeg-PNA
backbone in presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (EDCꢀHCl) and N-hydroxybenzotriazole (HOBt) to afford
ibu
Boc-aeg-(G )-PNA-OEt (8) in good yield. Ester 8, thus obtained, was
hydrolyzed under basic condition to afford the G-PNA monomer Boc-aeg-
ibu
(
G )–PNA–OH (9) monomer in good yield which was used to prepare a
[
18]
representative PNA (pG ) on solid phase using Boc-strategy (SI).
5

4
D. DATTA
Figure 1. Crystal structure of (A) tert-butyl(2-amino-6-chloropurin-9-yl)acetate 6 and (B) tert-
butyl[2-(isobutyryl)amino-6-chloropurin-9-yl]acetate 7 showing N9 isomer.
Figure 2. (A) Packing (2 ꢁ 2ꢁ2) along a-axis and (B) H-bond mediated ribbon like two-dimen-
tional array observed in single crystal structure along b-axis for intermediate 6.
Intermediate 6 was crystallized from a 1:1 mixture of EtOAc and petrol-
eum ether as yellowish white needles while excellent rod like crystals of 7
was seen from chloroform. Single crystal structures of intermediates 6
(
CCDC 1880599) and 7 (CCDC 1880600) confirmed the formation of
desired isomer 1 (Figure 1). It was noteworthy that both 6 and 7 were
purified thorough simple column chromatography through silica gel and
the solid pure compounds thus obtained, were crystallized easily in afore-
mentioned solvent systems. Different modes of H-bondings were observed
inside these crystals (Figures 2 and 3). For compound 6, eight-member
ring formation was seen between N1, N3 and NH of two adjacent guanine
2
bases (NH ꢀꢀꢀ N1 distance: 2.44 Å and NH ꢀꢀꢀ N3 distance: 2.97 Å). Apart
2
2
from that another H-bonding interaction was found observed between the
C¼O of tert-butyl ester and NH groups (C¼O ꢀꢀꢀNH distance: 2.38 Å)
2
2
(Figure 2B). On the other hand, intermolecular H-bonding was found
between isobutyryl group protected amide NH and N7 of two adjacent

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
5
Figure 3. (A) Packing (3 ꢁ 3ꢁ3) along b-axis incorporating CHCl molecules and (B) wavy inter-
3
molecular H-bond observed in single crystal structure along a-axis for intermediate 7.
guanines of 7 (average distance between amide NH ꢀꢀꢀN7 distance: 2.25 Å)
1
(
Figure 3B). H NMR data of 1 obtained from Schemes 1 and 2 exhibit
identical chemical shift values. Characteristic proton attached to C8 of
guanine appeared at 8.0 ppm whereas NH protons of N1 and 2-amino
group were found at 12.1 and 11.7 ppm, respectively (Figure 4). NMR
datum for 1 recorded in DMSO-d was in complete agreement with the
6
reported value of N9 regioisomer.
3
. Conclusions
In conclusion, the author has successfully synthesized N -(isobutyryl)-9-
carboxymethyl)guanine 1 exclusively through a modified synthetic route
2
(
which afforded regioselectively N9-analog with higher yields compared to
that of conventional procedure. Moreover, it reduces the reaction
2
time appreciably to make this important building block. N -(Isobutyryl)-9-
(
carboxymethyl)guanine obtained from this modified scheme was attached
to the aeg PNA backbone to obtain the G-PNA monomer Boc-aeg-
ibu
[18]
(
G )–PNA–OH which has successfully been used for Boc -strategy in
solid phase peptide synthesis (SPPS). This new reaction route is expected
to facilitate synthesis of PNA other organic molecules containing guanine,
the toughest among all other nucleobases.
4
. Experimental section
4
.1. General Experimental Procedure
All reagents were commercially purchased from Sigma Aldrich. Column
chromatographic separations were done using silica gel (100–200 mesh).
Solvents were dried and distilled following standard procedures. TLC was
carried out on pre-coated plates (Merck silica gel 60, f254) and the spots
1
were visualized with UV light. H NMR (400 MHz) and 13C NMR
(
100 MHz) spectra were recorded on Bruker and Jeol NMR spectrometer.
1
All H and 13C NMR were recorded in CDCl and DMSO-d . Chemical
3
6

6
D. DATTA
1
Figure 4. H NMR of 1 afforded from (A) conventional and (B) modified synthetic route in
DMSO-d recorded in 400 MHz instrument showing characteristic signals for N9-regioisomer.
6
shifts are reported in parts per million (ppm, d scale). If tetramethylsilane
(
TMS) was not present in the deuterated solvent, the residual protonated
solvent is referenced (CDCl , d 7.26; DMSO-d , d 2.50). Mass spectros-
3
6
copy data were obtained from Synapt G2QTof mass spectrometer in
þ
ESI mode. Melting points were determined in open-end capillary tubes
and are uncorrected. Single crystal X-ray diffraction (SCXRD, Bruker),
UV–Visible spectrophotometry (Perkin Elmer Lambda 45 double
beam UV–Vis spectrophotometer) data were collected for compound
characterization.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
7
4
.2. SCXRD study
4
.2.1. General procedure for crystallization
Single crystals X-ray studies were performed in Bruker D8 Venture single
crystal diffractometer in 4-circle goniometer configuration, equipped with
dual wavelength (Cu and Mo). InCoatec microfocus X-ray sources and
Photon 100 detector was used for data collection. Oxford Cryosystems’
Cryostream plus low temperature attachment (80–500 K) was used to keep
crystal at 100 K during data collection.
Samples were purified carefully before keeping for crystallization. Glass sam-
ple vials (2 mL) were washed with acetone and dried under a nitrogen gas
stream before use. PARAFILM “M” was used to close the vials. HPLC-grade
solvents were used for crystallization. The investigated single crystal was a
small-sized and the quality of diffraction was good. Numerous datasets were
collected on single crystals from different batches and one of the highest qual-
ities is reported herein. All non-hydrogen atoms were refined anisotropically.
H-atoms were placed at calculated positions and refined as riding atoms with
isotropic displacement parameters. Crystallographic data for the structures
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre and the deposition numbers are indicated.
4
.3. Synthesis
4
.3.1. tert-Butyl-(2-amino-6-chloropurin-9-yl)acetate 6
2
-Amino-6-chloropurine 5 (1.02g, 6.0mmol), K CO (0.87 g, 6.3 mmol) and
2 3
Cs CO (0.21 g, 0.63 mmol) were stirred under N , in DMF (20mL). Then
2
3
2
tert-butyl bromoacetate (0.93 mL, 6.3 mmol) was added dropwise, and the
resulting mixture was stirred for 17 h. The reaction mixture was suspended in
water (100mL) and the aq. layer was extracted with EtOAc (50ꢁ 3 mL). The
combined organic layer was washed with water and brine solution. The
organic layer was separated, dried over anhyd Na SO , filtered and the filtrate
2
4
was concentrated under reduced pressure. The crude mass thus obtained was
purified by column chromatography [Eluent: 20–70% of EtOAc in petroleum
ether] to afford compound 6 (1.45 g, 85%). Yellowish white solid; m.p.
ꢂ
1
ꢂ
1
2
63–166 C; H NMR (400MHz, DMSO-d , 25 C) d ¼ 8.09 (s, 1H), 6.96 (s,
6
ꢂ
H), 4.85 (s, 2 H), 1.41 ppm (s, 9 H); 13C NMR (100 MHz, DMSO-d , 25 C)
6
þ
d ¼ 166.7, 159.9, 154.3, 149.4, 143.6, 122.9, 82.3, 44.6, 27.7 ppm. HRMS (ESI ),
m/z calculated for (M þ H) C H ClN O : 284.0914, found: 284.0916.
11
15
5 2
4
.3.2. tert-Butyl[2-(isobutyryl)amino-6-chloropurin-9-yl]acetate 7
To a solution of tert-butyl-(2-amino-6-chloropurin-9-yl)acetate 6 (1.0 g,
ꢂ
3
.53 mmol) in pyridine (20 mL) at 0 C was added isobutyrylchloride (0.4 g,

8
D. DATTA
ꢂ
ꢂ
3
.75 mmol) at 0 C. The mixture was kept at 0 C for 1 h and then followed
by stirring at room temperature for 5 h. Saturated NaHCO solution
3
(
50 mL) was added to the reaction mixture followed by EtOAc (50 mL) and
the organic layer was partitioned. Aqueous part was washed with EtOAc
(
2 ꢁ 25 mL). The combined organic layer was dried over anhyd. Na SO ,
2
4
filtered and the filtrate was concentrated under reduced pressure. The
crude mass thus obtained was purified by column chromatography [Eluent:
1
0–50% EtOAc in petroleum ether] to afford compound 7 (1.12 g, 90%).
ꢂ
1
ꢂ
Yellowish white solid; m.p. 166–170 C; H NMR (400 MHz, CDCl , 25 C,
3
TMS) d ¼ 8.12 (bs, 1 H), 8.09 (s, 1 H), 4.90 (s, 2 H), 3.04–2.87 (m, 1 H),
1
2
3
.49 (s, 9 H), 1.28 ppm (d, J ¼ 6.9 Hz, 6 H); 13C NMR (100 MHz, CDCl ,
3
ꢂ
5 C, TMS) d ¼ 175.8, 165.7, 153.1, 152.2, 151.3, 145.2, 127.7, 84.2, 45.2,
þ
6.1, 28.1, 19.4 ppm; HRMS (ESI ), m/z calculated for (M þ H)
C H ClN O : 354.1333, found: 354.1338.
15
21
5 3
2
4
.3.3. N -(Isobutyryl)-9-(carboxymethyl)guanine 1
Compound 7 (1.0 g) was dissolved in 3:1 mixture of TFA:H O (10 mL) and
2
then stirred for 24 h at room temperature. The reaction mixture was evapo-
2
rated and triturated well with chilled diethyl ether to afford N -(isobu-
tyryl)-9-(carboxymethyl)guanine 1 (0.79 g, quantitative yield). White solid;
ꢂ
1
ꢂ
m.p. 200–205 C; H NMR (400 MHz, DMSO-d , 25 C) d ¼ 12.10 (s, 1 H),
6
1
1.69 (s, 1 H), 8.02 (s, 1 H), 4.91 (s, 2 H), 2.82–2.71 (m, 1 H), 1.11 ppm (d,
ꢂ
J ¼ 6.8 Hz, 6 H); 13C NMR (100 MHz, DMSO-d , 25 C) d ¼ 180.2, 169.0,
6
þ
1
54.7, 148.9, 148.2, 140.3, 119.3, 44.5, 34.7, 18.9 ppm. HRMS (ESI ), m/z
calculated for (M þ H) C H N O : 280.1046, found: 280.1052.
1
1
14 5 4
ibu
4
.3.4. Boc–aeg–(G )–PNA–OEt 8
[
6]
Compound 8 was synthesized following the known literature procedure
ꢂ
1
ꢂ
as white solid. M.p. 110–115 C; H NMR, (400 MHz, DMSO-d , 25 C)
6
d ¼ 12.08 (d, J ¼ 5.5 Hz, 1 H), 11.65 (d, J ¼ 7.6 Hz, 1 H), 7.83 (s, 0.7 H), 7.82
(
s, 0.3 H), 7.03 (t, J ¼ 5.5 Hz, 0.7 H), 6.76 (s, 0.3 H), 5.13 (s, 1.4 H), 4.97 (s,
0
3
1
9
.6 H), 4.42 (s, 0.6 H), 4.22 (q, J ¼ 7.1 Hz, 0.6 H), 4.08 (q, J ¼ 7.0 Hz, 2.8 H),
.50 (t, J ¼ 6.5 Hz, 1.4 H), 3.32 (d, J ¼ 11.9 Hz, 0.6 H), 3.24 (d, J ¼ 6.1 Hz,
.4 H), 3.02 (d, J ¼ 6.1 Hz, 0.6 H), 2.84–2.71 (m, 1 H), 1.37 (d, J ¼ 6.5 Hz,
H), 1.27 (t, J ¼ 7.1 Hz, 1 H), 1.17 (t, J ¼ 7.1 Hz, 2 H), 1.11 ppm (d,
ꢂ
J ¼ 6.7 Hz, 6 H); 13C NMR (100 MHz, DMSO-d , 25 C) d ¼ 180.2, 180.1,
6
1
1
3
69.5, 169.0, 167.0, 166.6, 155.8, 155.6, 154.9, 149.1, 149.2, 147.9, 147.9,
40.5, 140.4, 119.6, 78.2, 77.8, 61.3, 60.6, 49.1, 47.8, 46.9, 44.1, 43.9, 38.3,
þ
7.7, 34.7, 34.7, 28.2, 18.9, 14.0 ppm. HRMS (ESI ), m/z calculated for
(
M þ H) C H N O : 508.2520, found: 508.2535.
22
34 7 7

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
9
ibu
4
.3.5. Boc-aeg-(G )–PNA–OH 9
To a solution of compound 8 (0.25 g, 0.49 mmol) in tetrahydrofuran
(
0
10 mL) and distilled water (10 mL) was added LiOHꢀH O (0.03 g,
2
ꢂ
.74 mmol) at 0 C and the reaction mixture was stirred for 0.5 h. The aq
ꢂ
layer was adjusted to pH 3–4 with satd KHSO at 0 C and then extracted
4
with EtOAc (4 ꢁ 35 mL). The combined organic layer was dried over anhyd
Na SO and filtered. The filtrate was evaporated in vacuo and crude
2
4
product was purified by column chromatography [Eluent: 5–15% MeOH in
chloroform (CHCl )] to afford compound 9 (0.20 g, 85%) as a white solid.
3
ꢂ
1
ꢂ
M.p. 205–210 C; H NMR (400 MHz, DMSO-d , 25 C) d ¼ 12.14 (s,
6
0
.3 H), 12.12 (s, 0.7 H), 11.75 (s, 0.3 H), 11.70 (s, 0.7 H), 7.97 (s, 0.3 H), 7.95
(
s, 0.7 H), 7.05 (t, J ¼ 5.5 Hz, 0.7 H), 6.78 (t, J ¼ 5.2 Hz, 0.3 H), 5.14 (s,
1
1
3
.4 H), 4.98 (s, 0.6 H), 4.32 (s, 0.6 H), 4.00 (s, 1.4 H), 3.48 (t, J ¼ 6.6 Hz,
.4 H), 3.32 (t, J ¼ 6.8 Hz, 0.6 H), 3.24 (dd, J ¼ 13.2, 7.2 Hz, 1.4 H),
.07–2.98 (m, 0.6 H), 2.83–2.69 (m, 1 H), 1.36 (d, J ¼ 5.5 Hz, 9 H), 1.11
(
d, J ¼ 1.0 Hz, 3 H), 1.10 ppm (s, 3 H); 13C NMR (100 MHz, DMSO-d ,
6
ꢂ
2
1
4
5 C) d ¼ 180.2, 180.17, 170.8, 170.4, 166.8, 166.3, 155.8, 155.6, 154.6,
54.6, 149.2, 148.1, 140.6, 140.5, 118.94, 78.2, 77.8, 49.2, 48.6, 47.7, 47.0,
þ
6.8, 44.3, 44.1, 38.2, 37.6, 34.7, 34.69, 28.2, 28.17, 18.7 ppm. HRMS (ESI ),
m/z calculated for (M þ H) C H N O : 480.2206, found: 480.2213.
2
0
30 7 7
4
.3.6. Note
Synthesis of compound 6 is the key reaction step in this work as it
produced exclusive N9-regioisomer: tert-butyl-(2-amino-6-chloropurin-
9-yl)acetate. The principal driving force behind exclusive N9-regioisomer
formation is the stereo-electronic repulsion between the approaching bulky
electrophile (tert-butylbromoacetate) and the Cl-atom at 6-position of
2-amino-6-chloropurine. N9-Nitrogen, in contrast is more accessible to the
reagents under the reaction condition. Earlier, Debaene and Winssinger
2
reported the synthesis of N -benzhydryloxycarbonyl (Bhoc) protected
analog of 1 starting form 2-amino-6-chloropurine which involve a lengthy
[
19]
process
and suitable for only 9-fluorenylmethoxycarbonyl (Fmoc)-
[
20]
strategy
of SPPS. Although, K CO alone was used to generated N9-
2
3
[
19,21]
regioisomer from 2-amino-6-chloropurine and 6-chloropurine,
in this
report a mixture of K CO and Cs CO in 9:1 ratio to enhance the yield
2
3
2
3
of alkylation reaction significantly. It is well known that Cs CO is more
2
3
soluble in polar organic solvents (viz., DMF, DMSO, NMP) than any other
[
22]
[23]
alkali-metal carbonates.
Simultaneously, the “cesium ion effect”
played important role to facilitate the N-alkylation of purine nucleobase.
The ratio two bases (K CO and Cs CO ) was optimized after several
2
3
2
3
trial reactions where an effective inorganic base (Cs CO ) in organic
2
3
[
24]
reactions
improved the reaction yield at room temperature.

1
0
D. DATTA
Acknowledgments
DD thanks Department of Chemistry, IISER Pune for instrumental facilities. DD is also
thankful to Prof. Krishna N. Ganesh and DST SERB, India for National Post Doctoral
Fellowship (Project Code: PDF/2016/002510).
Conflicts of interest
There are no conflicts of interest to declare.
ORCID
Dhrubajyoti Datta
http://orcid.org/0000-0003-2077-1294
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